Perhexiline for treating chronic heart failure

ABSTRACT

Disclosed are methods for the treatment of chronic heart failure, comprising administering to an animal in need thereof an effective amount of perhexiline, or a pharmaceutically acceptable salt thereof, to treat said chronic heart failure. The chronic heart failure maybe non-ischaemic or ischaemic. Also disclosed is the use of perhexiline in the manufacture of a medicament to treat chronic heart failure, including chronic heart failure of a non-ischaemic origin and chronic heart failure of an ischaemic origin.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/244,103, filed Sep. 23, 2011, which is a continuation of U.S.application Ser. No. 10/592,250, filed on Sep. 8, 2006, (and afforded a35 U.S.C. 371(c)(1), (c)(2), and (c)(4) requirements date of receipt ofJul. 2, 2007), which is the National Stage of International ApplicationNo. PCT/GB2004/003835, filed Sep. 7, 2004, which claims the benefit ofGB 0405381.5, filed Mar. 10, 2004. The entire contents of each of theabove-identified applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Chronic heart failure (CHF) is associated with considerable morbidityand mortality despite recent advances in heart treatments. There are anumber of aetiological conditions that ultimately result in chronicheart failure including coronary artery disease, differentcardiomyopathies, hypertension, or valvular diseases. A detailedcharacterization of chronic heart failure as a clinical syndrome may befound in Hunt S A, Baker D W, Chin M H, Cinquegrani M P, Feldman A M,Francis G S, Ganiats T G, Goldstein S, Gregoratos G, Jessup M L, Noble RJ, Packer M, Silver M A, Stevenson L W. ACC/AHA guidelines for theevaluation and management of chronic heart failure in the adult: areport of the American College of Cardiology/American Heart AssociationTask Force on Practice Guidelines (Committee to Revise the 1995Guidelines for the Evaluation and Management of Heart Failure). 2001.American College of Cardiology(http://www.acc.org/clinical/guidelines/failure/hf_index.htm).

Coronary artery disease (obstruction or blockage of the arteries of theheart) leads to ischaemia; this is characterized by a lack of bloodsupply to tissues; in this case the heart. This lack of this essentialoxygen and nutrients can result in the tissue becoming impaired orpermanently damaged. Once damaged the cardiac tissue is unable toperform its function. As such, the strength and efficiency of the heartmuscle is reduced (this is technically termed left ventricular systolicdysfunction and results in a reduced ejection fraction; a measure of thepumping capacity of the heart). In addition to its ability to damage theheart muscle; cardiac ischaemia is frequently though not invariablyidentified by the physical symptom of angina (in some cases—ischaemiamay occur without the correlate of anginal chest pain). Angina typicallyoccurs under circumstances that would be expected to increase the heartsworkload; resulting in an increased requirement for energy. Thisincreased energy requirement necessitates increased oxygen provisionthat cannot be provided in the presence of arterial blockage; causingrelative ischaemia and hence pain. Exercise is a good example of this,where the output of the heart is increased but the blood supply does notmatch this increase in performance and thus some of the heart tissuebecomes ischaemic resulting in pain. This ischaemia, despite causingpain need not invariably result in irreversible heart damage and is notinvariably related to pump dysfunction. Although ischaemia can causeboth angina and heart failure, the exact manifestation of ischaemiarelates to its severity and time course. Ultimately ischaemia as aninciting influence for heart failure is dissociable from its capacity tocause angina; they may or may not co-exist.

However, a lack of blood supply is only one of the many causes forcardiac pump impairment. Other reasons include cardiac arrhythmias(abnormal heart electrical rhythms), hypertension (high blood pressure),valve diseases, infections, toxins or impairment in the nervousstimulation of the heart to name but a few.

While these initial insults to the heart are diverse in character andseverity, their common feature is that they cause either damage to heartmuscle cells (myocytes) or at least impair their ability to contract.This results in left ventricular systolic dysfunction. It is this commonfeature that triggers the cascade that results in the stereotyped anddistinct state of chronic heart failure. As discussed in “Mechanisms andModels in Heart Failure: A Combinatorial Approach”, by Douglas L. Mann,M D, Circulation, 1999; pages 999-1008 and in “Drug Therapy: TheManagement of Chronic Heart Failure”, by Jay N. Cohn, M D, New EnglandJournal of Medicine 1996; pages 490-498), heart failure may be viewed asa progressive disorder that is initiated after an index event eitherdamages the heart muscle, with a resultant loss 15 of functioningcardiac myocytes, or alternatively disrupts the ability of themyocardium to generate force, thereby preventing the heart fromcontracting normally. This index event may have an abrupt onset, as inthe case of a myocardial infarction (heart attack), it may have agradual or insidious onset, as in the case hemodynamic pressure orvolume overloading, or it may be hereditary, as in the case of many ofthe genetic cardiomyopathies.

Regardless and irrespective of the diverse nature of the inciting event,the feature that is common to all of these index events is that theyall, in some manner, produce a decline in pumping capacity of the heart.Following the initial decline in pumping capacity of the heart, acutely,patients may become very symptomatic; they may be minimally symptomaticor may even remain asymptomatic. However, the decreased pump capacitygenerally results in a diminished cardiac output. This chronicallyactivates the neurohumoral system, particularly the sympathetic nervoussystem, the renin-angiotensin-aldosterone system, and potentiates therelease of vasopressin.

Although in the short term these adaptations are beneficial due to theircapacity to maintain blood flow to vital organs; in the long term, thesereflexes have deleterious effects and ultimately result in cardiacremodeling (FIG. 1). This remodelling is the central stereotyped featureof CHF irrespective of the inciting influence and is manifest at themacroscopic level (visible to the eye) by dilatation of the heartchambers. However there is also corresponding remodelling at themolecular and the cellular level. These include changes in cellulartranscription (the genetic programmes determining cellular function) andthe resulting cellular pathways. One aspect of cellular function that isaltered in chronic heart failure is cellular metabolism and energyproduction.

The common unified programme of the failing heart irrespective of theinciting insult thus includes chronic energy starvation. It has beenpostulated that these energy changes are not simply just a feature ofCHF but are of mechanistic importance in chronic heart failure. Thefailing heart is characterized by a marked change in substratepreference away from fatty acid metabolism toward glucose metabolism.Glucose is a more efficient cellular fuel and this particular adaptationmay therefore be an adaptive feature of chronic heart failure—partiallymitigating the effect of energy deficit. It therefore follows thataugmentation of “metabolic remodeling” is a potential target in chronicheart failure; however to date there has been a paucity of even animaldata to confirm this assertion.

Perhexiline (2-(2,2-dicyclohexylethyl)piperidine) is a knownanti-anginal agent that operates principally by virtue of its ability toshift metabolism in the heart from free fatty acid metabolism toglucose, which is more energy efficient. Aside from being used for thetreatment of angina as a manifestation of ischaemia (in patients who mayor may not coincidentally have heart failure), there is no record ofusing perhexiline to treat instances of non-ischaemia and certainly noknown use of this drug to treat instances of heart failure independentof angina. Phrased alternatively; while perhexiline has been used totreat patients with angina and ischaemia at the point where this may bean inciting influence for heart failure as demonstrated by arrow (a) inFIG. 1, (which therefore may or may not be associated with activeischaemia-related pump dysfunction or ischaemia-related congestivecardiomyopathy); there has never been a suggestion that perhexiline maybe useful in the modification of chronic metabolic remodelling in thedistinct stereotyped phenotype of chronic heart failure as demonstratedby arrow (b) in FIG. 1.

With further reference to FIG. 1, it is apparent that there is aninciting phase of heart failure, which is due to diverse initiatinginfluences. While completely unrelated to one another, these diverseinfluences all result in pump failure and left ventricular systolicdysfunction. Irrespective of inciting influence, this pump failureinitiates an initially adaptive but ultimately partially maladaptiveremodelling. This chronic remodelling is a stereotyped molecular,cellular and macroscopic phenomenon, and the central cause of eventualprogressive chronic heart failure. Chronic heart failure remodellingultimately leads to a vicious cycle of detrimental events. Part of thechronic heart failure phenotype is energetic deficiency and a shift incellular metabolism away from fatty acid metabolism to glucosemetabolism.

SUMMARY OF THE INVENTION

Hitherto, perhexiline has been used as an anti-ischaemic agent atjuncture a, the inciting phase; although even at this stage it has notbeen used explicitly as an antifailure agent. The present inventionpostulates that metabolic manipulation with perhexiline is effective inmodifying not an inciting influence; but rather the common programme ofthe chronic heart failure state; hence this invention postulates a rolefor treating chronic heart failure at the distinct juncture b.

The present invention is thus based on the hypothesis thatperhexiline-induced metabolic modification may be beneficial totreatment of the stereotyped chronic heart failure state irrespective ofits effect on the inciting aetiology. The corollary of this assertionwould be that if indeed the effect of perhexiline is as a metabolicmodifier of CHF rather than a simple anti-ischaemic agent; its benefitin both ischaemically-induced CHF and non-ischaemically induced CHFwould be similar. The invention is supported by the first clinical datato show that any metabolic modifier (perhexiline in this case) iscapable of improving human chronic heart failure; furthermore thehypothesis is supported by the finding that the benefit of perhexilinein patients having ischaemic or non-ischaemic heart failure as assessedby improvements in a number of key indicators associated with chronicheart failure, was remarkably similar.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows how there is an inciting phase of heart failure.

FIG. 2 shows ³¹P MRS spectra of a right calf muscle at rest, during andafter exercise.

FIG. 3 shows data for primary and secondary end-points as discussed inthe “Results” section.

FIG. 4 shows data for primary and secondary end-points as discussed inthe “Results” section.

DETAILED DESCRIPTION OF THE INVENTION

According to a first aspect of the present invention, there is provideda method of treating chronic heart failure, which comprisesadministering to an animal in need thereof an effective amount ofperhexiline, or a pharmaceutically acceptable salt thereof, to treatsaid chronic heart failure. The animal is preferably a mammal and mostpreferably a human.

In one embodiment, said chronic heart failure may be chronic heartfailure as a result of an initial inciting influence of ischaemia.

In another embodiment, said chronic heart failure may be as a result ofan initial nonischaemic inciting influence, that is to say, chronicheart failure in the absence of significant coronary artery disease, asfor example may be determined by coronary angiography.

According to another aspect of the present invention, there is providedthe use of perhexiline in the manufacture of a medicament to treatchronic heart failure. In one embodiment, the medicament is for thetreatment of non-ischaemic chronic heart failure, that is chronic heartfailure in the substantial absence of inciting ischaemia. In anotherembodiment, the medicament is for the treatment of chronic heart failurehaving an ischaemic inciting origin.

In aspects of the present invention, the perhexiline exists in the formof a salt of perhexiline, preferably the maleate salt. The perhexilinemay be sued at doses in the normal therapeutic range for perhexiline(Kennedy J A, Kiosoglous A J, Murphy G A, Pelle M A, Horowitz J D.“Effect of perhexiline and oxfenicine on myocardial function andmetabolism during low-flow ischemia/reperfusion in the isolated ratheart”, J Cardiovasc Pharmacal 2000; 36(6):794-801).

Physiologically acceptable formulations, such as salts, of the compoundperhexiline, may be used in the invention. Additionally, a medicamentmay be formulated for administration in any convenient way and theinvention therefore also includes within its scope use of the medicamentin a conventional manner in a mixture with one or more physiologicallyacceptable carriers or excipients. Preferably, the carriers should be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof. Themedicament may be formulated for oral, buccal, parental, intravenous orrectal administration. Additionally, or alternatively, the medicamentmay be formulated in a more conventional form such as a tablet, capsule,syrup, elixir or any other known oral dosage form.

According to a further aspect of the invention there is provided atreatment programme for treating chronic heart failure, which involvesthe co-use or coadministration of perhexiline with one or more othercompounds that are advantageous in treating chronic heart failure or thesymptoms thereof. In one embodiment, the programme is for the treatmentof non-ischaemic chronic heart failure, that is chronic heart failure inthe substantial absence of inciting ischaemia. In another embodiment,the programme is for the treatment of chronic heart failure having anischaemic inciting origin.

EXAMPLE

An embodiment of the invention will now be described by way of exampleonly wherein a double-blind, randomised, placebo-controlled study wasundertaken in order to investigate the effects of perhexiline on chronicheart failure. 56 patients with CHF were recruited and all providedwritten informed consent. Entry criteria were as follows: leftventricular ejection fraction (LVEF) <40%, optimally medicated heartfailure with New York Heart Association (NYHA) Class II-III symptoms.Cardiopulmonary exercise testing with respiratory gas analysis,completion of the Minnesota Living with Heart Failure Questionnaire.(MLHFQ) and 2-D echocardiography were performed at baseline on allpatients.

Patients were then allocated to two groups (ischemic or non-ischemic)depending on the presence or absence of significant coronary arterydisease during coronary angiography.

The ischemic group (n=30) was also subjected to dobutamine stressechocardiography at baseline. The non-ischemic group (n=26) wassubjected to ³¹P magnetic resonance spectroscopy to measure changes inmuscle mitochondrial function.

All Patients: Cardiopulmonary Exercise Test

Incremental exercise testing with assessment of respiratory gas exchangewas performed on a treadmill using the Weber protocol. Breath by breathrespiratory gases were measured during exercise using a Pulmolab EX670system mass spectrometer which was calibrated before every study. Rawdata were averaged to 30 second intervals and oxygen consumption duringpeak exercise was obtained (V0₂max; ml/kg/min). Electrocardiograms andblood pressure were monitored throughout. Exercise was terminated at thesubject's request due to fatigue or breathlessness.

Minnesota Living with Heart Failure Questionnaire (MLHFQ)

A standard 21-question MLHFQ was employed to determine if perhexilineaffected patient quality of life. This is a well validated measure ofsymptomatology in heart failure (17) and includes questions to assessthe ability to perform activities of daily living as well as questionsgauging the severity of symptoms due to heart failure. Each question wasscored out of 5. The sum of the scores were calculated where a higherscore indicated a poorer quality of life. All patients completed thequestionnaires alone and without assistance.

Resting Echocardiography

Echocardiography was performed with patients in the left lateraldecubitus position using a Vingmed System V echocardiographic machineand a 2.5 MHz transducer. Images were stored digitally. Resting scanswere acquired using standard echocardiographic windows for LVEF,transmitral valve Doppler, and resting tissue Doppler. Tissue Dopplerechocardiography allows objective assessment of regional wall motion andis superior to conventional grey-scale echocardiography when used inconjunction with dobutamine stress (18).

Left ventricular volumes for calculation of LVEF were obtained usingbiplane echocardiography and the modified Simpson's formula. Volumeswere averaged over 3 beats. In addition, on-line tissue Doppler peaksystolic velocity (PSV) of the lateral mitral valve annulus was obtainedas a reflection of left ventricular long-axis function.

In theory, improving metabolic efficiency would also lead to animprovement in diastolic function of the left ventricle as energy isalso required for cardiac relaxation. The ratio of peak E wave fromtransmitral valve Doppler vs. the E wave from tissue Doppler of thelateral mitral valve annulus (E:EA ratio) is a sensitive indicator ofleft ventricular end diastolic pressure (19).

Ischemic Group:

Tissue Doppler assessment of the left ventricle was performed at restand analysed off-line using Echopac software in order to determineregional myocardial PSV from 15 left ventricular segments described indetail elsewhere (20). These segments were selected to include all areassupplied by the three major coronary arteries and for the greatestreproducibility for acquisition of PSV (21). (See FIG. 4)

Dobutamine Stress Echocardiography

Following resting echocardiography dobutamine infusion was commenced viaa syringe driver and incremented at 3 minute intervals from 5 mcg/kg/minto 10, 20, 30 and 40 mcg/kg/min. Digital loops of 15 views outlinedabove were stored at 90 seconds of each stage. Up to 1 mg of atropinewas given if the hemodynamic response was submaximal. Electrocardiogramsand blood pressure were monitored at each stage. End-points fortermination of the test were attainment of ≧85% of the target heartrate, evidence of ischemia, or severe side effects from dobutamine. Datafrom all stages were analysed off-line as with the resting images.

PSV data are expressed as velocity at rest, low dose dobutamine infusion(10 mls/kg/min) and peak dose dobutamine infusion (the last infusionstage before infusion terminated, which may include the addition ofatropine).

Non-Ischemic Group: ³¹P Magnetic Resonance Spectroscopy

Patients with CHF have abnormally rapid skeletal muscle phosphocreatine(a high energy phosphate metabolite critically involved in musclecontraction) depletion during exercise with delayed recovery(22). ³¹Pmagnetic resonance spectroscopy allows changes in skeletal muscleintracellular high energy phosphate compounds and pH to be measurednon-invasively. At the end of exercise, because glycogenolysis hasstopped and phosphocreatine resynthesis is purely oxidative, analysis ofphosphocreatine recovery provides information about skeletal musclemitochondrial function. In order to determine the effect of augmentingglucose metabolism on muscle energetics, magnetic resonance spectroscopyof calf muscle before, during and after local exercise was performed.Only patients in the nonischemic heart failure population were subjectedto magnetic resonance spectroscopy as underlying peripheral vasculardisease leads to abnormalities in skeletal muscle energetics independentof heart failure.

Skeletal muscle high-energy phosphate metabolism was measured using a2-Tesla superconducting whole-body magnet interfaced to a Bruker Avancespectrometer at least 3 days after the peak exercise tolerance test. Themethodology has been described in detail elsewhere (23).

Briefly, subjects were positioned within the magnet in the supineposition with a 6 cm diameter surface coil under the maximalcircumference of the right calf muscle. ³¹Phosphorus spectra werecollected at rest, during exercise and recovery. Following spectralacquisition at rest, a standardized exercise protocol was employed whichinvolved plantar flexion at 0.5 Hz lifting 10% of lean body mass adistance of 7 cm. This workload was continued for 4 minutes before beingincremented by 2% of lean body mass for every subsequent minute untilfatigue or phosphocreatine hydrolysis reached 50% of the resting level.Recovery spectra were subsequently acquired for 11 minutes. Examples ofthe spectra obtained during a typical study are shown in FIG. 3.

Phosphocreatine concentrations were quantified using a time-domainfitting routine (VARPRO, R. de Beer). Phosphocreatine recovery halftimefollowing exercise (PCr t½), a marker of skeletal muscle mitochondrialfunction which is independent of skeletal muscle mass and exerciseintensity, was calculated as previously described(24).

Intervention

Following baseline studies, patients were randomized in a double-blindfashion to receive either perhexiline (n=28) or placebo (n=28) 100 mgtwice daily. Blood was obtained at 1, 4, and 8 weeks after initiation ofthe drug for measurements of serum perhexiline levels with subsequentdose titration in order to prevent toxicity. Dose adjustments wereadvised as per a standard protocol by an unblinded physician. Identicaldosage adjustments were also made for randomly allocated placebo-treatedpatients by the unblinded observer in order to ensure blinding of theinvestigators was maintained. After 8 weeks of treatment, patients werere-evaluated as above.

Statistics

The primary end-point for this study was pre-defined as VO₂max with thefollowing secondary endpoints: MLHFQ score, LVEF, E:EA ratio, resting,low dose and high dose mean PSV during stress echocardiography and PCrt½. Therapy randomization of the ischemic and non-ischemic groupsoccurred separately but with similar protocols in order to allow forpre-hoc analysis of the primary endpoint in each group. The study had a95% power to detect a 2 ml/kg/min increase in V0₂max in the active vs.placebo groups with a significance level of 0.05. Data were analyzedwith SPSS 11.5 for Windows© and expressed as mean±standard error ofmean. ANCOVA using baseline values as covariates was performed to testfor significance of differences seen in the perhexiline vs. placebogroups following treatment. A p value of <0.05 was taken to indicatestatistical significance.

Results

All patients completed the 8-week course of treatment. There were nodeaths in either group during the study period. Side effects in theperhexiline group were restricted to transient nausea and dizzinessduring the first week of treatment (n=3).

Both groups were well matched for baseline characteristics and treatment(Table 1). There was a significant fall in the NYHA class within theperhexiline group after treatment (p=0.02).

VO₂max at baseline was similar in the perhexiline and placebo groups(Table 2). Following treatment, VO₂max was unchanged in the placebogroup but markedly increased by 2.7±0.8 ml/kg/min (16.7%) in theperhexiline group. ANCOVA demonstrated a significant effect ofperhexiline vs. placebo on VO₂max; p<0.001. The increase in VO₂max inthe ischemic and non-ischemic group were 2.9±1.2 ml/kg/min (p=0.008) and2.5±0.4 ml/kg/min (p=0.03) respectively. Exercise time tended toincrease in the perhexiline group.

MLHFQ scores were significantly reduced by 24.4% following treatment inthe perhexiline group (p=0.04) but unchanged in the placebo group.Perhexiline therapy was also associated with a significant reduction inPCr t½ (from 67±15 to 44±7 seconds; p<0.05) in the non-ischemic group.The normal range for PCr t½ in normal healthy adults is 14 to 50 seconds(23).

Mean LVEF was also markedly increased following treatment in theperhexiline group (by 9.9+2.0 absolute percentage points, a relativeincrease of 42%) and unchanged in the placebo group (p<0.001). Whilstleft ventricular diastolic volume tended to decrease in the perhexilinegroup (p=0.06), systolic volume was significantly reduced (p<0.001)suggesting an increase in myocardial contractility. There was asignificant reduction in E:EA ratio following treatment with perhexilinereflecting a reduction in left ventricular end diastolic pressure. Inaddition long-axis systolic function was increased in the perhexilinegroup reflecting an improvement in subendocardial function.

Within the ischemic cohort, there was no significant difference in heartrate at rest or during dobutamine stress in both groups. However, therewas a significant 15% (p=0.04) increase in resting mean PSV in theperhexiline group following treatment. This increase reflects theincreases seen in long-axis function and LVEF. During tissue Dopplerstress echocardiography; there was a trend towards an increase in PSV atbaseline (p=0.07) in the perhexiline group but a marked increase in peakdose PSV (24% p=0.03). At lower doses of dobutamine the myocardialvelocities are inevitably lower; these low velocities are furtherdiminished when measured off-line when compared to those obtainedon-line by pulsed tissue Doppler. This is because they are derived fromregional mean velocities rather than peak velocities. Though standardpractice; this diminution will artificially appear to diminish thesignificance of the differences at low myocardial velocities. Thisexplains the contrast between the seemingly small differences inbaseline and low dose stress tissue Doppler parameters compared to theconsistent and large increases in LVEF and online PSV of the lateralmitral annulus.

The data for the primary and secondary end-points are depicted on FIGS.3 and 4 and summarized on Table 2.

Discussion

As a result of these experiments, it was found that Perhexiline useresulted in significant improvements in peak exercise capacity,myocardial function at rest and stress, patient reported symptoms andskeletal muscle energetics. Remarkably; as well as being statisticallyhighly significant, these improvements represent clinically significantimprovements in patients who were already optimally treated. Our resultssuggest that perhexiline provides consistent improvements in theseparameters, in the absence of significant side effects, irrespective ofthe initial inciting influence of CHF.

Without wishing to be bound by theory, the mechanism for the improvementseen in myocardial function with perhexiline is likely to be related toinhibition of FFA uptake and a metabolic shift towards the use ofglucose and lactate. This may restores the failing hearts insulinsensitivity and makes it more oxygen efficient. In addition to requiringmore oxygen than glucose to generate energy, excessive FFA metabolismhas other potentially detrimental effects on the heart. FFA metabolismis known to uncouple oxidative phosphorylation and suppresses glucoseoxidation through a direct inhibitory action on the glycolytic pathway.This inhibition causes increases lactate and proton accumulation withinmyocardial cells (Lopaschuk G O, Wambolt R B, Barr R L. “An imbalancebetween glycolysis and glucose oxidation is a possible explanation forthe detrimental effects of high levels of fatty acids during aerobicreperfusion of ischemic hearts”, J Pharmacal Exp Ther 1993;264(1):135-144) leading to a fall in intracellular pH which isassociated with a reduction in contractile function (Hausch G.“Hibernating myocardium”, Physiol Rev 1998; 78(4):1055-1085).Furthermore, FFA metabolite accumulation have been shown to reduceventricular arrhythmia threshold (Murnaghan M F. “Effect of fatty acidson the ventricular arrhythmia threshold in the isolated heart of therabbit” Br J Pharmacal 1981; 73(4):909-915) and induce diastolicdysfunction (Depre C, Vanoverschelde J L, Taegtmeyer H. “Glucose for theheart”, Circulation 1999; 99(4):578-588.).

The anti-anginal efficacy of perhexiline, both as mono- and combinedtherapy, is well documented (Horowitz J D, Mashford M L. “Perhexilinemaleate in the treatment of severe angina pectoris”, Med J Aust 1979; 1(11):485-488; Cole P L, Beamer A D, McGowan N, Cantillon C O, Benfell K,Kelly R A et al. “Efficacy and safety of perhexiline maleate inrefractory angina. A double-blind placebo-controlled clinical trial of anovel antianginal agent”, Circulation 1990; 81(4):1260-1270). However,use of the drug declined due to reports of hepatotoxicity and peripheralneuropathy. It is now apparent that the risk of toxicity was related tothe ability to metabolize the drug. ‘Slow hydroxylators’, with a geneticvariant of the cytochrome P450-2D6, are particularly prone toprogressive drug accumulation. In the absence of dosage adjustment;prolonged elevation of levels leads to phospholipid accumulation whichmay also occur with prolonged use of other CPT inhibitors, such asamiodarone. The risk of development of hepato-neuro-toxicity withperhexiline is markedly reduced by monitoring and maintaining serumlevels between 0.15 and 0.60 mg/l. None of the patients in this studydeveloped abnormal liver function tests or neuropathy as a consequenceof perhexiline treatment followed by close serum level monitoring andtitration.

³¹P magnetic resonance spectroscopy was included in the study design todetermine whether perhexiline treatment also improved skeletal muscleenergetics. PCr t½ is a muscle bulk and workload independent marker ofskeletal muscle mitochondrial function. The faster phosphocreatinerecovery after exercise in the perhexiline treated patients suggested animprovement in skeletal muscle mitochondrial oxidative function. Thismay reflect an improvement in the heart failure syndrome and/or be adirect consequence of the metabolic substrate shift in skeletal muscle.

The results of the current study therefore establish that perhexilineexerts incremental benefits on symptomatic status, left ventricularfunction at rest and peak stress, and skeletal muscle metabolism inpatients with stable chronic heart failure, over and above standardneurohumoral therapy. Indeed, the improvements in VO₂max were comparableto those seen in patients treated with beta-blockers (Hulsmann M, SturmB, Pacher R, Berger R, Bojic A, Frey B et al. “Long-term effect ofatenolol on ejection fraction, symptoms, and exercise variables inpatients with advanced left ventricular dysfunction”, J Heart LungTransplant 2001; 20(11):1174-10 1180) but exceeded those seen with ACEinhibitors (Vescovo G, Della L L, Serafini F, Leprotti C, Facchin L,Volterrani M et al. <<Improved exercise tolerance after losartan andenalapril in heart failure: correlation with changes in skeletal musclemyosin heavy chain composition”, Circulation 1998; 98(17):1742-1749),spironolactone (Cicoira M, Zanella L, Rossi A, Golia G, Franceschini L,Brighetti G et al. “Long-term, dose-dependent effects of spironolactoneon left ventricular function and exercise tolerance in patients withchronic heart failure”, J Am Coli Cardiel 2002; 40(2):304-310) or evenwith biventricular pacing (Auricchio A, Stellbrink C, Butter C, Sack S,Vogt J, Misier A R et al. “Clinical efficacy of cardiacresynchronization therapy using left ventricular pacing in heart failurepatients stratified by severity of ventricular conduction delay”, J AmColi Cardiel 2003; 42(12):2109-2116). As this study included patientswith and without significant coronary artery disease who all benefited,the benefit cannot therefore be ascribed purely to an anti-ischemicmechanism, rather, it is suggestive of our hypothesis that Perhexilineis modifying the central metabolic remodeling of CHF.

The contents of all references cited herein are hereby incorporatedherein in their entirety for all purposes.

TABLE 1 Baseline characteristics and treatment Placebo Group PerhexilineGroup N 28  28  Ischemic:Non Ischemic 13:15 13:15 Age 63 ± 2 63 ± 2 Sex(M:F) 23:5  27:1  Weight (kg) 83 ± 3 89 ± 3 Height (cm) 165 ± 6 cm 175 ±2 cm Body mass index 28 ± 1  29 ± 1  NYHA Class Pre:  2.2 ± 0.1 2.4 ±0.1 Post:  2.1 ± 0.1  1.9 ± 0.2⁺ Corrected QT interval Pre: 421 ± 7 ms413 ± 11 ms  Post: 421 ± 9 ms 413 ± 13 ms  Diabetes 2 5 Loop Diuretic20  17  ACE Inhibitor 25  22  Lisinopril (mean dose)  22 ± 4 mg  23 ± 3mg Ramipril 10 mg  8.3 ± 1 mg Perindopril  6 mg  6 mg Enalapril 22 ± 10mg  15 ± 5 mg Trandolapril  4 mg  4 mg AT2 Receptor Blockers 4 3Losartan 63 ± 38 mg 100 mg  Valsartan 80 mg 80 mg Irbersartan 175 ± 125mg  — Beta-Blockers 15  18  Carvedilol 37 ± 10 mg 50 mg Bisoprolol  2 ±0.4 mg  4 ± 1 mg Metoprolol 75 ± 25 mg 100 mg  Atenolol 67 ± 17 mg 69 ±19 mg Aspirin 15  11  Clopidogrel 1 3 Warfarin 9 9 Calcium ChannelBlockers 5 3 Spironolactone (mean dose) 7 (21 ± 4 mg) 6 (23 ± 2 mg)Amiodarone 4 1 Oral Hypoglycaemics 1 2 Insulin 0 2 Statin 18  12  Serumperhexiline levels: Week 1: 0 0.57 ± 0.19 mg/l  Week 4: 0 0.67 ± 0.20mg/l  Week 8: 0 0.43 ± 0.12 mg/l  ⁺p = 0.02

TABLE 2 Primary and secondary endpoints. (All P values refer to AN CO VAof the differential effect of perhexiline vs. placebo) PerhexilinePlacebo Group Group P value VO₂max (ml/kg/min) Pre: 16.3 ± 0.8 16.1 ±0.6 *<0.001 Post: 16.0 ± 0.9  18.8 ± 1.1* Exercise Time (mins) Pre:  9.9± 1.2 10.5 ± 1.2 Post: 10.9 ± 0.9 12.3 ± 1.1 Respiratory exchange ratioduring peak exercise⁺ Pre:  1.1 ± 0.02  1.1 ± 0.03 Post:  1.1 ± 0.02 1.1 ± 0.03 Resting BP (mmHg) Pre: 111/63 ± 5/3  116/69 ± 7/4  Post113/67 ± 5/4  113/67 ± 7/4  Peak Exercise BP (mmHg) Pre: 141/69 ± 5/4 141/75 ± 9/3  Post: 137/68 ± 7/4  142/70 ± 9/5  Resting HeartRate(min⁻¹) Pre: 76 ± 4 73 ± 3 Post: 78 ± 4 73 ± 3 Peak Exercise HeartRate(min⁻¹) Pre: 124 ± 6  121 ± 6  Post: 121 ± 5  120 ± 5  Minnesotaliving with heart failure questionnaire score Pre: 42 ± 5 45 ± 5^(†)0.04 Post: 40 ± 4  34 ± 5^(†) Left ventricular end-diastolic volume(ml) Pre: 213 ± 16 232 ± 11 Post: 216 ± 16 212 ± 9  Left ventricularend-systolic volume (ml) Pre: 159 ± 13 176 ± 8  ^(‡)<0.001 Post: 162 ±14 140 ± 8^(‡ ) Left ventricular ejection fraction (%) Pre: 26 ± 1 24 ±1 ^(§)<0.001 Post 26 ± 1  34 ± 2^(§) Long axis function (cm/s) Pre:  6.4± 0.6  5.8 ± 0.4 ^(||)0.04 Post:  6.4 ± 0.5  7.2 ± 0.6^(||) E:EA RatioPre:  8.3 ± 1.0  8.8 ± 0.6^(#) ^(#)0.02 Post:  8.9 ± 1.8 6.5 ± 0.9 PCr1½ (seconds) Pre:  58 ± 10  67 ± 15 **<0.05 Post:  73 ± 24  44 ± 7**Dobutamine Stress Echocardiography: Heart Rate: Rest Pre 67 ± 5 57 ± 2Post 66 ± 6 53 ± 2 Low Dose Pre 86 ± 8 78 ± 7 Post 74 ± 6 65 ± 6 PeakDose Pre 130 ± 5  126 ± 4  Post 128 ± 5  122 ± 3  Mean PSV (15 segments)Rest Pre  3.5 ± 0.2  3.3 ± 0.2 ^(††)0.07 Post  3.4 ± 0.2   3.8 ±0.2^(††) ^(§§)0.003 Low Dose Pre  4.6 ± 0.3  4.7 ± 0.3 Post  4.8 ± 0.3 5.0 ± 0.5 Peak Dose Pre  6.4 ± 0.4  6.6 ± 0.5 Post  5.8 ± 0.4   8.2 ±0.8^(§§) ⁺Ratio of CO₂ emission/oxygen consumption

What is claimed is:
 1. A method for treating a mammal having chronicheart failure or a symptomatic component/feature/condition thereof dueto or associated with a member of the group consisting of: ischaemia,coronary artery disease, cardiomyopathy, hypertension, diabetes, andvalvular disease, the method comprising: diagnosing the mammal as havingchronic heart failure or a symptomatic component/feature/conditionthereof; and administering to said mammal a therapeutically-effectiveamount of perhexiline.
 2. The method of claim 1, wherein thetherapeutically-effective amount of perhexiline is sufficient to reduceor ameliorate the chronic heart failure or a symptomaticcomponent/feature/condition thereof in the mammal.
 3. The method ofclaim 1, wherein the perhexiline is in the form of a pharmaceuticallyacceptable salt.
 4. The method of claim 2, wherein the perhexiline is inthe form of a maleate salt.
 5. The method of claim 1, wherein the mammalis a human.
 6. The method of claim 1, further comprisingco-administering to said mammal at least one therapeutic compound. 7.The method of claim 1, further comprising co-administering to saidmammal at least one therapeutic compound advantageous in treatingchronic heart failure or a symptomatic component/feature/conditionthereof.
 8. The method of claim 6, wherein the therapeutic compound isselected from a member of the group consisting of Alpha Blockers, BetaBlockers, Calcium Channel Blockers, Diuretics, Ace(Angiotensin-Converting Enzyme) Inhibitors, Arb (Angiotensin II ReceptorBlockers), Spironolactone, Nitrate, Warfarin, Verapamil, Insulin,Amiodarone, Lisinopril, Ramipril, Perindopril, Enalapril, Trandolapril,At2 Receptor Blockers, Losartan, Valsartan, Irbersartan, Carvedilol,Bisoprolol, Metoprolol, Atenolol, Aspirin, Clopidogrel, OralHypoglycaemics, Disopyramide, and Statins.
 9. The method of claim 1,wherein the symptomatic component/feature/condition is member of thegroup consisting of dyspnoea (shortness of breath), chest pain, fatigue,palpitation, and syncope.
 10. The method of claim 1, wherein thesymptomatic component/feature/condition is member of the groupconsisting of reduced left ventricular ejection fraction (LVEF), reducedE:EA ratio, abnormally rapid skeletal muscle phosphocreatine depletionwith delayed recovery, reduced systolic velocity (PSV), diminishedexercise capacity or tolerance, diminished peak oxygen consumption(VO₂max) during exercise, and impaired myocardial energetic state(PCr/γATP ratio).
 11. The method of claim 1, wherein the extent ofchronic heart failure in the mammal is diagnosed in accordance with theNew York Heart Association (NYHA) diagnostic system.
 12. The method ofclaim 9, further comprising: determining a NYHA classification score(breathlessness) of the mammal before and after administration ofperhexline, wherein a decreased NYHA score after administration ofperhexline indicates a reduction in the extent of chronic heart failureor a symptomatic component/feature/condition thereof in the mammal. 13.The method of claim 12, wherein the NYHA classification score of themammal after administration of perhexline decreases from Class III toClass II.
 14. The method of claim 1, wherein the extent of chronic heartfailure in the mammal is diagnosed in accordance with the MinnesotaLiving with Heart Failure Questionnaire (MLHFQ) scoring system.
 15. Themethod of claim 14, further comprising determining a MLHFQ (quality oflife) score of the mammal before and after administration of perhexline,wherein a decreased MLHFQ score after administration of perhexlineindicates a reduction in the extent of chronic heart failure or asymptomatic component/feature/condition thereof in the mammal.
 16. Themethod of claim 1, further comprising determining peak oxygenconsumption (VO₂max) in the mammal during exercise wherein an increasein peak oxygen consumption (VO₂max) in the mammal after administrationof perhexline indicates a reduction in the extent of chronic heartfailure or a symptomatic component/feature/condition thereof in theanimal.
 17. The method of claim 1, wherein perhexiline is administeredin an amount of 300 mg per day or less.
 18. The method of claim 1,wherein perhexiline is administered in an amount of 100 mg per day orless.
 19. The method of claim 1, wherein perhexiline is administered inan amount of 100 mg to 300 mg per day.
 20. The method of claim 1,further comprising: monitoring and maintaining serum levels ofperhexiline in said mammal in a range of about 0.15 and about 0.60 mg/l.21. A method for treating chronic heart failure substantially asdescribed in the specification, Tables and Examples, with reference toeach of the accompanying Figures.